E-cadherin downregulation in cancer occurs frequently and is clearly a pivotal event in the transition to metastasis. Interestingly, recent studies of nearly all of the major human tumor types also reveal frequent downregulation of p120, but the mechanism and consequences of p120 downregulation are unknown. Moreover, p120 downregulation in tumors has been largely ignored because until recently there was no compelling reason to focus on the issue. This proposal is based primarily on three key observations, two of which are included as preliminary data. First, p120 is required for E-cadherin stability. Second, p120 expression is frequently downregulated or regionally absent in a significant subset of the most common human cancers (eg, colon, prostate, lung, breast, and others). Third, DN-cadherins strongly promote tumor progression and/or metastasis in animal models, and probably act via sequestering p120. The data provides compelling evidence that p120 downregulation might contribute to E-cadherin downregulation in a subset of human tumors. We have constructed a conditional p120 knockout (KO) mouse (conventional p120-KO is embryonic lethal), providing the first opportunity to examine p120 function in vivo, and the consequence(s) of p120 downregulation in disease and/or cancer. The mouse intestinal epithelium is an excellent model for studying normal p120 function, and the Min (APC mutation) and Azoxymethane (AOM) mouse models for colon cancer are ideally suited for studying p120 downregulation in cancer. However, disease and tumor modifiers also can have distinct tissue specificities that are essentially unpredictable. To address these issues, (1) We will determine the consequences or p120-loss under otherwise normal conditions using a villin-CreER transgene to control the timing and extent of p120 KO in the gastrointestinal (Gl)-tract. (2) We will directly identify the consequences of p120 downregulation in colon cancer by targeting p120-loss to the Gl-tract in the context of Min and AOM mouse cancer models. (3) We will generate a stochastic p120-deleter mouse model to induce accelerated LOH and address at the whole animal level the hypothesis that p120 is a critical disease and/or tumor modifier in susceptible tissues. Together, these experiments directly address the consequences of p120 downregulation in disease and cancer, and may lead to increased understanding of events mediating the transition to metastasis.